WO2001060768A1 - Process for producing cyclic compound - Google Patents

Abstract

A process suitable for safely mass-producing, through a short step, cyclic compounds useful in medicines, agricultural chemicals, foods, cosmetics, and chemical products or as intermediates therefor. The process, which is for producing a compound represented by the formula (I) or a salt thereof: {wherein Z represents an electron-attracting group; W represents optionally substituted ethylene or optionally substituted vinylene; R3 represents hydrogen or an optionally substituted hydrocarbon group; and X represents a divalent group [provided that when W represents optionally substituted vinylene, then -X-CH¿2?-Z is not -X?1-X2-CH¿2-Z (wherein X1 represents sulfur or optionally substituted nitrogen and X2 represents optionally substituted ethylene)]}, is characterized by subjecting a compound represented by the formula (II) or a salt thereof: (wherein the symbols have the same meanings as the above) to a ring closure reaction in a solvent containing a carbonic diester.

Description

 Description Method for producing cyclic compound

 The present invention relates to a method for producing a cyclic compound useful as a pharmaceutical, an agricultural chemical, a food, a cosmetic, a chemical, or an intermediate thereof. Background art

 Conventionally, a cyclic compound is synthesized by, for example, (1) a method using an intramolecular Friedel-Crafts reaction (eg, Japanese Patent Application Laid-Open No. 57-192379), and (2) a method using a cyclic acrylic acid derivative. Is a method of synthesizing a diester derivative by subjecting it to ring closure by a Dieckmann-type cyclization reaction, followed by reduction and dehydration reactions (J. Chem. Res., Synop., (1987), (12), 394-5, etc.) ), (3) In the case of cyclic alkene derivatives, methods based on intramolecular WitUg reaction (eg, W098 / 55475) have been reported.

 However, intermediates useful in J. Heterocyclic Chem., 31, 351-355 (1994), Heterocycles, 49, 215-232 (1998), J. Heterocyclic Chem., .33, 1909-1913 (1996), etc. Despite various disclosures, it is generally difficult to synthesize cyclic compounds (especially, cyclic compounds having eight or more membered rings), and at present, even when synthesis is possible, the yield is low. Was.

 In view of the above situation, a cyclic alkene derivative can be led to various derivatives such as a cyclic ketone derivative or a cyclic acrylic acid derivative by its characteristic structure. It is possible to use easy and inexpensive raw materials, and to use reagents that do not cause disposal problems and reagents that are suitable for large-scale synthesis. Is desired. · Disclosure of the invention

As a result of various studies, the present inventors have found that using an active methylene derivative as an intermediate, The inventors have found that a cyclic alkene derivative can be produced inexpensively and easily by performing a cyclization reaction in the presence of an acid diester, and as a result of further studies based on these findings, the present invention has been completed.

 That is, the present invention

 (1 set

[In the formula, Z represents an electron-withdrawing group, W represents optionally substituted ethylene or optionally substituted vinylene, and when the ethylene or vinylene has two substituents, May combine to form an optionally substituted ring, R ³ represents a hydrogen atom or an optionally substituted hydrocarbon group, and X represents a divalent group (preferably a linear group). a divalent group) Imuko number 3 or more parts (however, when W represents a good vinylene substituted, over _ (11 ₂ - 2 - ¹ - ² - (11 ₂ -2

(Wherein, X ¹ represents a sulfur atom or a nitrogen atom which may be substituted, and X ² represents ethylene which may be substituted).) The compound represented by the formula: A ring closure reaction in a solvent,

 Wherein each symbol is as defined above, or a method for producing a salt thereof;

(2) The production method according to the above (1), wherein X is a divalent group having 1 to 12 (preferably, 3 to 12) atoms in the straight-chain portion;

(3) The production method according to the above (1), wherein Z is an esterified hepoxyl group; (4) The production method according to the above (1), wherein R ³ is a hydrogen atom;

 (5) The method according to the above (1), wherein the reaction is carried out in the presence of a base;

(6) The production method according to the above (5), wherein the base is an alcoholate;

 Equation (7)

[In the formula, Z represents an electron withdrawing group, and R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, or an optionally substituted thiol. A group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, wherein R ¹ and R ² may combine to form an optionally substituted ring, and R ³ represents A hydrogen atom or an optionally substituted hydrocarbon group; a combination of a dashed line and a solid line represents a single bond or a double bond; and X is a divalent group (preferably a straight-chain moiety having 3 or more atoms. (However, when the combination of the dashed line and the solid line indicates a double bond, one X—CH ₂ _Z is one X ¹ —X ² _CH ₂ —Z (where X ¹ is a sulfur atom or X represents an optionally substituted nitrogen atom, and X ² represents an optionally substituted ethylene) Wherein the compound represented by the formula (1) or a salt thereof is subjected to a ring-closure reaction in a solvent containing diethyl carbonate.

 Wherein each symbol is as defined above, or a method for producing a salt thereof;

(8) The production method according to the above (7), wherein X is a divalent group having 1 to 12 (preferably, 3 to 12) atoms in the linear portion;

(9) The production method according to the above (7), wherein Z is an esterified hepoxyl group; (10) The production method according to the above (7), wherein R ³ is a hydrogen atom;

 (11) The method according to (7), wherein the reaction is performed in the presence of a base;

(12) The production method according to the above (11), wherein the base is an alcoholate;

 Equation (13)

[Wherein, Z represents an electron withdrawing group, R ³ represents a hydrogen atom or a hydrocarbon group which may be substituted, a combination of a dashed line and a solid line represents a single bond or a double bond, and ring A is substituted X represents a divalent group (preferably, a divalent group having 3 or more atoms in the linear portion) (provided that ring A may be substituted X_CH ₂ — Z is — X ¹ — X ² — CH ₂ — Z (where X ¹ is a sulfur atom or may be substituted) Represents a nitrogen atom, and X ² represents ethylene which may be substituted.) The compound represented by the formula or a salt thereof is subjected to a ring closure reaction in a solvent containing a carbonic acid diester.

 Wherein each symbol is as defined above, or a method for producing a salt thereof;

(14) The production method according to the above (13), wherein X is a divalent group having 1 to 12 (preferably 3 to 12) atoms in the straight-chain portion;

 (15) The production method according to the above (1.3), wherein Z is an esterified hydroxyl group;

(16) The production method according to the above (13), wherein R ³ is a hydrogen atom;

 (17) The production method according to (13), wherein the reaction is performed in the presence of a base;

(18) The production method according to the above (17), wherein the base is an alcoholate;

[In the formula, Z represents an electron-withdrawing group, W represents optionally substituted ethylene or optionally substituted vinylene, and when the ethylene or vinylene has two substituents, May combine with each other to form an optionally substituted ring, R ³ represents a hydrogen atom or an optionally substituted hydrocarbon group, and X ″ represents a straight-chain moiety having 4 or more atoms having 2 or more atoms. Or a salt thereof;

 (20) The compound according to (19), wherein X "is a divalent group having 4 to 6 atoms in the straight-chain portion;

(21) The compound according to (19), wherein Z is an esterified carboxyl group; (22) the compound according to (19), wherein R ³ is a hydrogen atom;

 Equation (23)

[In the formula, Z represents an electron withdrawing group, and R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, or an optionally substituted thiol. A group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, wherein R ¹ and R ² may combine to form an optionally substituted ring, and R ³ represents Represents a hydrogen atom or an optionally substituted hydrocarbon group, a combination of a dashed line and a solid line represents a single bond or a double bond, and X "represents a divalent group having 4 or more atoms in the straight-chain portion.] Or a salt thereof; (24) The compound according to the above (23), wherein X "is a divalent group having 4 to 6 atoms in the straight-chain portion;

(25) The compound according to (23), wherein Z is an esterified carboxyl group; (26) the compound according to (23), wherein R ³ is a hydrogen atom;

 Equation (27)

[Wherein, Z represents an electron withdrawing group, R ³ represents a hydrogen atom or a hydrocarbon group which may be substituted, a combination of a dashed line and a solid line represents a single bond or a double bond, and a ring Α X represents an optionally substituted ring, and X "represents a divalent group having 4 or more atoms in the straight-chain portion] or a salt thereof;

 (28) The compound according to the above (27), wherein X "is a divalent group having 4 to 6 atoms in the straight-chain portion;

(29) The compound according to the above (27), wherein Z is an esterified propyloxyl group; (30) the compound according to the above (27), wherein R ³ is a hydrogen atom.

As used herein, the term “electron withdrawing group” includes, for example, (i) a carboxyl group which may be esterified or amidated, (ii) a formula — (CO) R ⁴ (wherein R ⁴ Represents hydrogen or a hydrocarbon group which may be substituted), (iii) nitrile group, (iv) nitro group, and (V) Formula (SO _m ) R ⁵ (wherein m represents 1 or 2, and R ⁵ represents a hydrocarbon group which may be substituted.) (vi) a group represented by the formula: PR ⁶ R ^{7 wherein} R ⁶ and R ⁷ are each substituted (Vii) a group represented by the formula: (vii) a formula (PO) (OR ⁸ ) (OR ⁹ ), wherein R ⁸ and R ⁹ are each hydrogen or substituted A hydrocarbon group which may be substituted), (viii) an aryl group which may be substituted, (ix) an alkenyl group which may be substituted, (X) a halogen atom ( For example, fluorine, Iodine, bromine, iodine, etc.), (xi) nitroso group, preferably rather is esterified or amidated which may be force Rupokishiru group of the formula - (C_〇) R Ί

Groups represented by ^4, nitrile group, a nitro group, the formula _ (SO _m) the group represented by R ^5, a group represented by the formula -PR ⁶ R ^7, wherein ^{- (PO) (OR 8)} ( A group represented by OR ⁹ ), more preferably an esterified carboxyl group (eg, a methoxyl-carbonyl, ethoxycarbonyl, tert-butoxycarbonyl-esterified alkyloxy group).

The “esterified carboxyl group” in the “esterified or amidated carboxylic acid group” of the above (i) is represented by the formula (CO) OR ^{1 Q} (where R ^1Q is a substituted And a group represented by an amidated carbonyl group, which is represented by the formula — (CC NRUR ¹² (wherein R ¹¹ and R ¹² are respectively Represents hydrogen or a hydrocarbon group which may be substituted, and R ¹¹ and R ¹² are bonded to each other and have a 57-membered (preferably 56-membered) cyclic amino group together with an adjacent nitrogen atom (eg, tetrahydropyrrole, Radiazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.).

In the formula of the (vi) or (vii), R ⁶ and R ⁷ or R ⁸ and R ^9, taken together, for example, lower (C ₂ one ₆₎ alkylene (e.g., dimethylene, trimethylene styrene, tetra methylene etc.), lower (C ₂ - ₆₎ alkenylene (e.g., one CH ₂ - CH = CH-, one _{CH 2 - CH 2 - CH =} CH-, one _{CH 2 - CH = CH_ CH 2} - , etc.), lower (C ₄ _ ₆₎ Arukajie two alkylene (e.g., - CI-I = CH- CH = CH- , etc.), etc., preferably lower (C ₆₎ alkylene, more preferably lower (C ₂ one ₄₎ § alkylene formed may have, these divalent groups may have a substituent, and examples of the substituent, for example a hydroxyl group, halogen, C ^ - ₄ alkyl. ^ 4 alkoxy and the like.

As "Ariru group" in the optionally substituted Ariru group of the (viii), for example, phenyl, C _6, such as naphthyl - such as ₁₄ Ariru, preferably C ₆ - E. Aryl, and more preferably phenyl. The aryl group may have 13 substituents similar to the substituents that the “optionally substituted hydrocarbon group” may have.

The “alkenyl group” in the optionally substituted alkenyl group of the above (ix) Te is, for example, vinyl, Ariru (allyl), crotyl, 2 one pentenyl, an alkenyl having 2 to 10 carbon atoms such as xenon alkenyl to 3, such as preferably a lower (C ₂ _ ₆₎ alkenyl Le, more preferably Bulle And the like. The alkenyl group may have one to three substituents similar to the substituents that the “optionally substituted hydrocarbon group” described below may have.

 As the “hydrocarbon group” in the “optionally substituted hydrocarbon group” used in the present specification, for example,

(1) Alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc .; alkyl, Preferably lower (such as (^ _ ₆ ) alkyl);

(2) cycloalkyl (for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₃ _ ₇ cycloalkyl such as heptyl and the like cyclohexylene);

(3) alkenyl (e.g., vinyl, Ariru (allyl), crotyl, 2 _ pentenyl, alkenyl having 2 to 10 carbon atoms, such as cyclohexenyl 3, preferably lower (C ₂ _ ₆₎ an alkenyl and the like);

 (4) Cycloalkenyl (for example, C3-C7 cycloalkenyl such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl);

(5) alkynyl (for example, Echeru, 1 one propynyl, 2 _ propynyl, 1 one Bucheru, 2-pentynyl, alkynyl of 2 to 10 carbon atoms such as hexynyl to 3, preferably lower (C ₂ - ₆₎ alkynyl such as And the like);

(6) Ariru (. E.g., phenyl, C 6 ₄ Ariru naphthyl, etc., preferably Ariru, more preferably like phenyl);

(7) Ararukiru (e.g., phenylene Lou CI- ₄ alkyl (e.g., benzyl, and the like Fuene chill etc.)); and the like. Among these, alkyl rather preferable, d_ methyl, such Echiru ₄ Alkyl is more preferred, and methyl is particularly preferred.

The hydrocarbon group may have a substituent. Examples of the substituent include, for example, Halogen (e.g., fluorine, chlorine, bromine, iodine), nitro, Shiano, hydroxyl, optionally substituted thiol group (e.g., thiol, C ^ - ₄ alkylthio, etc.), an optionally substituted amino group ( Eg, amino, monoalkylamino, di

— 4- to 6-membered cyclic amino such as _4- alkylamino, tetrahydropyrrol, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), esterified or amidated Lipoxyl group (e.g., carboxyl,

(Such as ^ _ ₄ alkoxyl-rubamoyl, mono-alkyl-rubumoyl, di-alkyl-rubumoyl), alkyl optionally substituted by halogen atom or alkoxy (eg, trifluoromethyl, methyl, ethyl, etc.), Alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.) which may be substituted with a halogen atom or alkoxy, formyl, c ₂ _ ₄ alkanol (eg, acetyl, propionyl, etc.), alkyl Sulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.),

C i _ ₄ alkylsulfinyl (e.g., methane sulfinate El, etc. E evening Nsurufiniru) and the like. The number of substituents, 1 to 3 are preferred.

In the above formula, “ethylene” and “vinylene” in “optionally substituted ethylene” and “optionally substituted vinylene” represented by W are represented by the formula — CH ₂ — CH ₂ — and the formula —CH = CH-divalent group. These divalent groups may have a substituent at a substitutable position. Examples of such a substituent include a “halogen atom” represented by R ¹ and R ² described below, and "Good amino group", "optionally substituted hydroxyl group", "optionally substituted thiol group", "optionally substituted hydrocarbon group", "optionally substituted heterocyclic group" And the like groups. When the ethylene or vinylene has two substituents, the substituents may be bonded to each other to form an optionally substituted ring. Further, R ¹ and R ² may combine to form an optionally substituted ring. Here, examples of the optionally substituted ring include the same rings as the optionally substituted ring (preferably an optionally substituted benzene ring and the like) as ring A described below.

In the above formula, the “halogen atom” represented by R ¹ and R ² includes, for example, Element, chlorine, bromine and iodine.

In the above formula, the `` optionally substituted amino group '' represented by R <sup>1</sup> and R <sup>2</sup> includes the above-mentioned `` optionally substituted hydrocarbon group '' And the number of substituents may be any of 0 to 2. When two substituents are present, the two substituents may be the same or different. In addition, the two substituents are bonded to each other to form a 5- to 7-membered (preferably 5- to 6-membered) cyclic amino group (eg, tetrahydropyrrole, piperazine, piperidine, morpholine, thiol) Morpholine, pyrrole, imidazole, etc.). In the above formula, the `` optionally substituted hydroxyl group '' represented by R <sup>1</sup> and R <sup>2</sup> includes, for example, the above-mentioned `` optionally substituted hydrocarbon group '' which may be substituted with a hydroxyl group. .

In the above formula, examples of the `` optionally substituted thiol group '' represented by R <sup>1</sup> and R <sup>2</sup> include a thiol group optionally substituted by the aforementioned `` optionally substituted hydrocarbon group '' Is mentioned.

In the above formula, the “heterocycle” in the “optionally substituted heterocyclic group” represented by R ¹ and R ² is a heteroatom 1 selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like. 5 to 7-membered aromatic heterocyclic ring containing at least 1 (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2), saturated or unsaturated non-aromatic Group heterocycle (aliphatic heterocycle) and the like.

Here, the “aromatic heterocyclic ring” is a 5- to 6-membered aromatic monocyclic heterocyclic ring (for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazolyl, isothiazole, imidazole, pyrazolo) 1,2,3-oxaziazol, 1,2,4-oxaziazol, 1,3,4-oxaziazol, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazol , 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.) Examples of the “non-aromatic complex ring” include 5 to 7 such as pyrrolidine, tetrahydrofuran, thiolane, piberidine, tetrahydropyran, morpholine, thiomorpholine, piperazine and pyran. Member (preferably 5-6 members) saturated or unsaturated (preferably saturated) A non-aromatic heterocycle (aliphatic heterocycle) and the like, or a 5- to 6-membered non-aromatic heterocycle in which part or all of the above-mentioned aromatic monocyclic heterocycle is saturated with a double bond, The heterocyclic ring is preferably a 5- to 6-membered aromatic ring, and more preferably furan, thiophene, pyrrole, pyridine (preferably a 6-membered ring) and the like.

 Examples of the substituent that the heterocyclic ring may have include the same substituents as the substituent that the aforementioned “optionally substituted hydrocarbon group” may have, and the like. The number may be one to three.

In the above formula, Z is preferably an esterified carboxy. Group, R ³ is preferably a hydrogen atom, and R ¹ and R ² are a hydrogen atom or an optionally substituted hydrocarbon. R ¹ and R ² are preferably bonded to each other to form an optionally substituted benzene ring.

 As the substituent which the “optionally substituted benzene ring” used in the present specification may have, the above-mentioned “optionally substituted hydrocarbon group” may have the optional substituent A substituent similar to the group; a substituent (for example, a divalent group having 1 to 4 atoms constituting a straight-chain portion) which may be bonded through a spacer An aryl group which may be substituted (preferably, an aryl group which may be directly substituted, or the above-mentioned aryl group which may be substituted). preferable. Examples of the number of substituents include 1 to 4.

Here, “spacer” is, for example, one (CH ₂ ) _a — [& represents an integer of 1 to 4 (preferably an integer of 1 to ₂ )], and one (CH ₂ ) _b -X '- [b are integers of 0 to 3 (preferably an integer from 0 to 1) indicates, X' is optionally substituted imino group (e.g., lower (^ - ₆₎ lower alkyl, lower ( C ₃ - ₇₎ cycloalkyl, formyl, lower (C ₂ - ₇₎ lower Arukanoiru, lower ((: lower alkoxy - such as good an imino group optionally substituted by carbonyl), carboxymethyl group, an oxygen atom or oxidation Represents a sulfur atom (eg, _S (0) _n — (n is an integer of 0 to 2) etc.),, — CH-CH—, one C≡C—, -CO-NH- , — S〇 ₂ — NH— and the like (preferably one (CH ₂ ) b—X′—, more preferably one CH ₂ — 0—). Benzene ring " The right or left Although it may be a joint, it is preferable to bond with the “optionally substituted benzene ring” via the right hand.

Examples of the ring formed by the bonding of R ¹ and R ² and the “optionally substituted ring” represented by A in the above formula include C ₅ _ ₇ cycloalkane (eg, cyclopentane, cyclo hexane, cycloheptane, etc.), C ₅ _ ₇ Shikuroarugen (eg, -1-cyclopentene, 2-cyclopentene, 3-cyclopentene, key sensor to 2-cyclopropyl, cyclohexene, etc., to 3-cyclopropyl), C ₅ _ ₆ Shikuroaruka 5- to 7-membered (preferably 5- to 6-membered) saturated or unsaturated alicyclic ring such as a diene (eg, 2,4-cyclopentadiene, 2,4-cyclohexadiene, 2,5-cyclohexadiene, etc.) Formula hydrocarbons; 6 to 14-membered aromatic hydrocarbons such as benzene, naphthylene, azulene, and acenaphthylene; 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen (preferably Is one or two A 5- to 7-membered aromatic heterocyclic ring, saturated or unsaturated non-aromatic heterocyclic ring (aliphatic heterocyclic ring) containing at least one (preferably 1 to 4, more preferably 1 to 2) And the like.

 Here, the “aromatic heterocyclic ring” is a 5- to 6-membered aromatic monocyclic heterocyclic ring (for example, furan, thiophene, pyrrol, oxazole, isoxazole, thiazol, isothiazole, imidazole, pyrazole, 1 , 2,3- Oxaziazol, 1,2,3-thiadiazol, 1,2,3-triazol, pyridine, pyridazine, pyrimidine, pyrazine, etc.) and the like, and "non-aromatic heterocycle" Examples thereof include a 5- to 7-membered (preferably 5- to 6-membered) saturated or unsaturated non-aromatic compound such as pyrrolidine, tetrahydrofuran, thiolane, piperidine, morpholine, thiomorpholine, tetrahydropyran, piperazine and pyran. 5- or 6-membered member in which the double bond is partially or entirely saturated in an aromatic heterocyclic ring (aliphatic heterocyclic ring) or the above-mentioned aromatic monocyclic heterocyclic ring. Such as a non-aromatic heterocyclic ring.

In addition, the ring formed by the bonding of R ¹ and R ² and the “optionally substituted ring” represented by A in the above formula may be formed by condensing 2 to 3 (preferably 2) single rings described above. Thus, a condensed ring may be formed. Preferred examples of such a condensed ring include two identical or different heterocyclic rings (preferably one heterocyclic ring and one aromatic heterocyclic ring, more preferably two identical or different two heterocyclic rings). Ring fused with aromatic heterocycle); 1 ring A ring obtained by condensing a heterocyclic ring with one homocyclic ring (preferably, one heterocyclic ring and one benzene ring, and more preferably, one aromatic heterocyclic ring and one benzene ring); Specific examples of such a condensed ring include, for example, indole, benzothiophene, benzofuran, benzimidazole, imidazo [1,2-a] pyridine, quinoline, isoquinoline, cinnoline and the like.

As the ring formed by the bonding of R ¹ and R ² and the “optionally substituted ring” represented by A, a 5- to 6-membered aromatic ring is preferable, and benzene, furan, thiophene, and And pyridine (preferably a 6-membered ring) are preferred, and benzene is particularly preferred.

The ring formed by R ¹ and R ² and the ring A may each have a substituent, and the substituent includes the “benzene ring” in the “optionally substituted benzene ring” described above. And the same substituents as the substituents which may be possessed, and 1 to 3 identical or different substituents may be substituted at any substitutable position.

 In the above formula, the “divalent group” represented by X is preferably a divalent group having 3 or more atoms in the straight-chain portion.

Expression

Or expression

In formula (I), any ring may be used as long as it can form a 5- to 16-membered ring (preferably a 5- to 12-membered ring, more preferably a 7- to 10-membered ring, particularly preferably an 8- to 10-membered ring). That is, X may be any divalent group having 1 to 12 (preferably 1 to 8, more preferably 3 to 6, and particularly preferably 4 to 6) atoms in the straight-chain portion. As a specific example, for example,

(1) — (C¾) _al _ (al is an integer of 1 to 12, preferably 3 to 12.), — (CH ₂ ) _a2 (CH = CH) one (CH ₂ ) _a3- (a2, And a3 are the same or different and each represent an integer of 0 to 10, provided that the sum of a2 and a3 is 10 or less, preferably 1 to 10), — (C) _a4 (CH = C = CH) A (CH ₂ ) _a5- (a4 and a5 are the same or different and each represent an integer of 0 to 9; however, the sum of a4 and a5 is 9 or less),

(2) One (C) _bl — Y— (CH ₂ ) _b2 — (M and b2 are the same or different and each represents an integer of 0 to 11. However, the sum of bl and b2 is 11 or less, preferably 2 to is a 11 Y represents 0, S, and NH), one _{(C¾) b3 -. Y- (} CH 2) b4 - (CH = CH) one (CH _{2) b5} - or single (CH _{2) b5} - ( _{CH = CH) - (CH 2} ) b4 -Y- (CH 2) b3 - 0) 3, b4 and b5 represents an integer of 0 to 9 are the same or different. However, the sum of b3, b4 and b5 is 9 or less. Y represents 0, S, NH), one (CH ₂ ) _b6 — Y— (CH ₂ ) _b7- (CH = C = CH) — (CH ₂ ) _b8 — or one (CH ₂ ) _b8 — ( CH = C = CH) One (CH ₂ ) _b7 — Y— (CH ₂ ) _b6 — (b6, b7 and b8 are the same or different and each represents an integer of 0 to 8. However, the sum of b6, b7 and b8 Is less than or equal to 8. Y indicates 0, S, NH),

(3)-(CH ₂ ) _cl- (N = CH)-(CH ₂ ) _c2- (cl and c2 are the same or different and each represent an integer of 0 to 10. However, the sum of cl and c2 is 10 or less. , Preferably 1 to 10), one (CH ₂ ) _c3 — (N = CH)-(CH ₂ ) _c4 — (CH = CH) — (CH ₂ ) _c5 — or one (CH ₂ ) _c5 — ( CH = CH) 1 (CH ₂ ) _{c 4} (N = CH) 1 (CH ₂ ) _c3- (c3, c and c5 are the same or different and each represents an integer of 0 to 8, provided that c3, c4 and c5 Is less than or equal to 8), one (CH ₂ ) _e6 — (N = CH) one (CH ₂ ) _c7 One (CH = C = CH) one (CH ₂ ) _c8 — or one (CH ₂ ) _c8 — (CH = C = CH) — (CH ₂ ) _c7 — (N-CH)-(CH ₂ ) _c6 one ( c6, c7 and c8 are the same or different and each represent an integer of 0 to 7, provided that the sum of c6, c7 and c8 is 7 or less),

_{(4) - (CH 2)} dl - (CH = N) - (CH 2) d2 -. (Dl and d2 is an integer of Do or different 0, however, the sum of dl and d2 10 Hereinafter, preferably 1 to 10), one (C¾) _d3 one (CH = N)-, (C¾) _d4 — (CH = CH)-(CH ₂ ) _d5 — or one (CH ₂ ) _d5 — ( CH = CH) one _{(C¾) d4 - (CH =} N) one _{(C¾) d3 -. (d3} , d and d5 represents an integer of the same or different 0-8, respectively, however, d3, the sum of d and d5 is 8 or less), one _{(C¾) d6 - (CH =} N) one _{(CH 2) d7 - (CH} = OCH) - (CH 2) d8 - or single _{(CH 2) d8 - (CH} = C = _{CH) - (CH 2) d7} - (CH = N) - (CH 2) d6 -. (d6, d7 and d8 represents an integer of 0 to 7 are the same or different and provided that the sum of d6, d7 and d8 Is 7 or less),

(5)-(CH ₂ ) _eI- (N = N)-(CH ₂ ) _e2- (el and e2 are the same or different!) To 10 are integers. However, el and e2 and the sum of 10 or less, preferably _{1~10), - (C¾) e3} - (N = N) one _{(CH 2) e4 - (CH} = CH) one (CH _{2) e5} - or single (C¾) _e5 - the (e3, e4 and e5 is an integer of the same or different 0-8, respectively - (CH = CH) - ( CH 2) e4 - (N = N) - (CH 2) e3 Where the sum of e3, e4 and e5 is 8 or less), _ (CH ₂ ) _e6 — (N = N) — (CH ₂ ) _e7- (CH-C = CH)-(CH ₂ ) _{e8 —Or} one (CH ₂ ) _e8 _ (CH = C = CH) — (CH ₂ ) _e7 _ (N = N) — (CH ₂ ) _e6 — (e6, e7 and e8 are the same or different and are 0 to 7 Where the sum of e6, e7 and e8 is 7 or less),

_{(6) - (CH 2)} "- Y- (CH 2) f2 - (N = CH) - (CH 2) f3 - (fl, f2 and f3 is an integer of 0-9 is the same or different. and伹, the sum of fl, f2 and f3 are 9 or less and Y is 0, 'S, the _{Saku), -. (C¾) t3} - (N = CH) - (CH 2) f2 -Y- (CH ₂ ) _fl- (fl, f2 and f3 are the same or different and each represent an integer of 0 to 9. However, the sum of Π and f3 is 9 or less. Y represents 0, S, NH),-( _{C¾) f4 - (CH = CH} ) - (CH 2) [5 -Y- (C¾) f6 - (n = CH) one _{(C¾) n - (f4,} f5, f6 and f7 are the same or different 0 and.伹an integer of 7, the sum of f4, f5, f 6 and f 7 is 7 or less. Y represents 0, S, and M), one _{(CH 2) f8 -Y- (CH} 2) _{f9 - (CH = CH) -} (CH 2) no - (N = CH) - (C¾) m -. (f8, f9, Π0 and Π1 is an integer of the same or different 0-7, however, f8, The sum of f9, 'Π0 and fll is not more than 7. Y indicates 0, S, NH), one (C¾) _fl2 — Y— (CH ₂ ) _fl3 — (N = CH) — (C¾) „ ₄ -(CH = CH)-(CH ₂ ) _fl5- (Π2, fl3, Π4 and Π5 are the same or different and represent an integer of 0 to 7. However, the sum of Π2, Π3, f14 and f15 is 7 or less. ), (CH ₂ ) _f7- (N = CH)-(CH ₂ ) _f6 -Y- (CH ₂ ) _f5- (CH = CH)-(CH ₂ ) _r4- (f4, f5, f 6 And Π are the same or different and represent an integer of 0 to 7, provided that the sum of f4, 〖5, f6 and f7 is 7 or less, Y represents 0, S, NH), one (CH ₂ ) _{fll - (N = CH) -} (C¾) fl0 - (CH = CH) one _{(CH 2) f9 - Y -} (CH 2) [8 - (f8, f9, Π0 and fll are the same or different 0-7 represents an integer of However, f8, f9, the sum of Π0 and Π1 is 7 or less Υ represents 0, S, a ΝΗ), -.. (CH 2) ng - (CH = CH) - (CH 2) _{[ 14-} (N = CH)-(CH ₂ ) _{fl3 -Y-} (CH ₂ ) _fl2- (fl2, fl3, f14 and f15 are the same or different and each represent an integer of 0 to 7, provided that The sum of fl2, fl3, Π4 and fl5 is 7 or less),

_{(7) - (CH 2)} gl -Y- (CH 2) g2 - (CH = N) - (CH 2) g3 - (gl, g2 and g3 is an integer of 0-9 is the same or different. However, the sum of gl, g2 and g3 is not more than 9. Y indicates 0, S, NH),-(CH ₂ ) _g3- (CH = N)-(CH ₂ ) _g2 -Y- (CH ₂ ) _gl- (gl, g2 and g3 are the same or different and represent an integer from 0 to 9. However, the sum of gl, g2 and g3 is 9 or less. Y represents 0, S, M),-( (CH ₂ ) _g4- (CH = CH)-(CH ₂ ) _g5 -Y- (CH ₂ ) _g6- (CH = N) one (CH ₂ ) _g7 — (g4, g5, g6 and g7 are the same or different represents an integer of 0-7. in伹, g4, g5, the sum of the g6 and g7 are 7 or less. Y represents 0, S, and NH), one _{(CH 2) g8 -Y- (CH} 2) _{g9 - (CH = CH) -} (C¾) gl0 - (CH = N) - (CH 2) gll -. (g8, g9, glO and gll is an integer of the same or different 0-7, however, g8, The sum of g9, glO and gll is not more than 7. Y indicates 0, S, NH),-(CH ₂ ) _{gl2 -Y-} (CH ₂ ) _gl3- (CH = N)-(CH ₂ ) _gl4 _ (CH = CH) _ (C¾) _gl5- (gl2, gl3, gl4, and gl5 are the same or different and represent integers from 0 to 7. However, the sum of gl2, gl3, g, and gl5 is 7 or less.) , — (CH ₂ ) _g7- (CH = N)-(CH ₂ ) _g6 -Y- (CH ₂ ) _g5- (CH = CH)-(CH ₂ ) _g4- (g4, g5, g6 and g7 are the same Or differently, and represents an integer of 0 to 7, provided that the sum of g4, g5, g6 and g7 is 7 or less, Y represents 0, S, NH), and one (CH ₂ ) _gll- (CH = N )-(CH ₂ ) _gl . One (CH = CH) one (C¾) _g9 — Y one (CH ₂ ) _g8 — (g8, g9, glO and gll are the same or different and represent integers from 0 to 7. However, g8, g9, glO and gll the sum of 7 or less and Y is 0, S, and _{NH), -. (CH 2} ) gl5 - (CH = CH) - (CH 2) gl4 - (CH = N) - (CH 2) gl3 - Y- (CH ₂ ) _gl2- (gl2, gl3, gl4 and gl5 are the same or different and represent integers from 0 to 7, provided that gl2, gl3, gl4 and gl5 Is less than or equal to 7),

_{(8) - (C¾) hl} -Y- (CH 2) h2 - (N = N) - (C¾) h3 -. (Hi, h2 and h3 is an integer of 0-9 is the same or different, however, The sum of hi, h2 and h3 is not more than 9. Y indicates 0, S, NH), one (C) _h3 — (N = N) _ (C¾) _h2 — Y— (C¾) _hl — (hi , h2 and h3 are the same or different and each represent an integer of 0 to 9. However, the sum of hi, h2 and h3 is not more than 9. Y represents 0, S and NH),-(C¾) _h4 - (CH = CH) - ( CH 2) h5 - Y- (CH 2) h6 - (N = N) - (C¾) h7 one (h4, h5, h6 and h7 are the same or different 0-7 integer are shown, however, h4,, the sum of h5, h6 and h7 is 7 or less and Y is 0, S, and _{NH), _ (C¾) h8} _Y_ (CH 2) h9 -.. (CH = CH) - _{(CH 2) hl0 - (N} = N) -. (CH 2) h n- (h8, h9, hlO and hll is an integer of 0 to 7 is the same or different, however, h8, h9, M0 and hll Is less than or equal to 7. Y represents 0, S, NH), one (C¾) _hl2 _Y_ (CH ₂ ) _hI3- (N = N)-(CH _{2) hl4 - (CH = CH} ) - (CH 2) hl5 -. (Hl2, hl3, hl4 and HL5 is an integer of the same or different 0-7, however, hl2, hl3, M4 and the sum of HL5 7 ), — (CH ₂ ) _h7 — (N = N) — (CH ₂ ) _h6 — Y — (CH ₂ ) _h5 — (CH = CH) — (CH ₂ ) _h4 — (h4, h5, h6 and h7 are the same or different and represent an integer of 0 to 7 provided that the sum of h4, h5, h6, and h7 is 7 or less and Y is 0, S, indicating a NH), -.. (CH 2) hll - (N = N) - (CH 2) hl0 - a (h8, h9, hlO and hll is an integer of the same or different and 0~7 - (CH-CH) - (C¾) h9 -Y- (CH 2) h8 Show. However, the sum of h8, h9, hlO and hll is 7 or less. Y represents 0, S, NH), — (CH ₂ ) _hl5 — (CH-CH) — (CH ₂ ) _hl4 — (N = N) — (CH ₂ ) _hl3 — Y— (C) _hl2 — ( hi2, hi3, hl4 and hi5 are the same or different and represent an integer from 0 to 7. However, the sum of hl2, hl3, Μ4 and hl5 is 7 or less.

(9)-(C¾) _η -Υ'- (CH ₂ ) _j2 -Y ^2- (CH ₂ ) _j3- ( _jl , j2 and j3 are the same or different and represent an integer of 0 to 10; 1,] '2 and the sum of j 3 is 10 or less, preferably. 1 to 10 Y ¹ is and Y ² respectively 0, S, and _{M), -. (CH 2} ) j4 - Y 4 _ (C¾) _j5 one ^{_{Y 5 - (CH 2) j6}} - Y 6 - (CH 2) j7 -. (j4, j5, j 6 and] '7 denote the same or different an integer from 0 to 9, however, j4 ,] · 5,] · 6 and] '7 are not more than 9. Υ ⁴ , Υ ⁵ , Υ ⁶ and Υ ⁷ represent 0, S, ΝΗ, respectively) and the like. For example, _0—, 1 0 1 (C¾) _kl 1 (kl is up to 5, preferably 2 to 5), 1 0— CH = CH_, — 0— CH ₂ CH = CH—, 1 0— CH = CH—C¾—, — (CH ₂ ) _kl — 0— (kl is an integer of 1 to 5, preferably 2 to 5), —CH = CH—0—, —CH “CH = CH—0—, — CH = CH— CH ₂ — 0_, -S-, one S— (CH ₂ ) _k2- (k2 is an integer of 1 to 5, preferably 2 to 5), —S— CH = CH—, — S— C — CH = CH—, — S— CH = CH— CH ₂ — , One (C¾) _kl —S— (kl is an integer of 1 to 5, preferably 2 to 5), one CH = CH—S—, one C one CH = CH_S—, one CH = CH—CH ₂ — S —, —NH—, —NH— (CH ₂ ) _k2 — (k2 is an integer of 1 to 5, preferably 2 to 5), —NH—CH = CH—, — NH—CH ₂ CH—CH—, — NH— CH = CH— C¾ one, one (CH ₂ ) _kl — NH— (kl is an integer from 1 to 5, preferably 2 to 5), — CH = CH_NH—, -C¾-CH = CH-NH- — CH = CH— CH ₂ — NH—, one (C¾) _k2 — (k2 is an integer of 1 to 5, preferably 2 to 5), -CH = CH-, _C¾— CH—, -CH = CH one CH ₂ —, _N = CH-, — CH = N—, one N = N—, — C¾— N = CH—, one CH ₂ — CH = N—, — C¾ one N = N—, _N = CH_C—, Examples include divalent groups such as CH = N_CH ₂ _, —N = N—CH ₂ —, etc., but preferably 1— (CH ₂ ) _kl _ (kl is 1 to 5, preferably 1 to 5). Or 2 to 5, more preferably an integer of 3 to 5), one S— (C) _k2 — (k2 is 1 to 5, preferably 2 to 5, more preferably an integer of 3 to 5) ), _NH— (C) _k2 — (k2 is an integer of 1 to 5, preferably 2 to 5, more preferably 3 to 5), _ (C) _k2 — (k2 is 1 to 5, preferably 2 to 5, more preferably an integer of 3 to 5), one (CH ₂ ) _kl — 0— (kl is an integer of 1 to 5, preferably 2 to 5, and more preferably an integer of 3 to 5); CH ₂ ) _kl — S— (kl is 1 to 5, preferably 2 to 5, more preferably 3 to 5), _ (CH ₂ ) _kl —NH— (kl is 1 to 5, preferably 2 to 5) 5, more preferably an integer of 3 to 5), and more preferably 10— (CH ₂ ) ₂ —, 10— (C¾) ₃ —, 10— (CH ₂ ) ₄ —, 0— (C¾) ₅ —, one S— (CH ₂ ) ₃ —, — S_ (C¾) ₄ —, one S_ (C¾) ₅ _, one NH— (CH ₂ ) ₃ —, — NH— (CH ₂ ) ₄ —, —NH— ( C¾) ₅ — and the like. The divalent group may have a substituent, and the substituent may be any as long as it can bind to the divalent group. Examples of the substituent include R ¹ and R ^2. Halogen atom, optionally substituted amino group, optionally substituted hydroxyl group, optionally substituted thiol group, optionally substituted hydrocarbon group, optionally substituted heterocyclic group, etc. Is mentioned. Further, the substituents may be bonded to each other to form a ring together with the divalent group. Examples of such a ring are the same as those formed by bonding R ¹ and R ^2. Is done. In the above-mentioned “divalent group” represented by X, when the atom constituting the straight-chain portion is a sulfur atom, the sulfur atom may be oxidized, and specifically, , -SO- and - S0 ₂ - may be either. Furthermore, the substituents of R ¹ and X or R ² and R ³ are combined to form an optionally substituted ring. The ring may be the same as the optionally substituted ring formed by combining R ¹ and R ² . When the substituents of R ¹ and X are bonded to form an optionally substituted ring, the first to third (preferably the first to second, More preferably, the substituent on the ^first atom) and R ¹ are bonded.

Further, in the “optionally substituted ethylene” or the “optionally substituted vinylene” represented by W, the “ethylene J or“ vinylene J ”substituent and the X substituent or R ³ are bonded. May form an optionally substituted ring, and examples of such a ring are the same as the optionally substituted ring formed by combining R ¹ and R ² . When the substituent of “ethylene” or “vinylene” and the substituent of X are bonded to form a ring, the first to third (preferably, 1 to 2) positions in the straight-chain portion of X bonded to ethylene or vinylene It is preferred that the substituent on the (third, more preferably the first) atom be bonded to the substituent on "ethylene" or "vinylene".

 In the above formula, the combination of “dashed line and solid line” indicates a single bond or a double bond (preferably, a double bond).

 Further, when the compound having the substituent is a basic compound according to the type of the substituent exemplified above, it can be converted to a salt using an acid according to a conventional method. Such an acid may be any acid as long as it does not hinder the reaction. For example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, and sulfamic acid, and formic acid Acetic acid, trifluoroacetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, succinic acid, malic acid, organic acids such as P-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, etc., and acidic amino acids such as aspartic acid and glutamic acid. Is mentioned. When the obtained compound is a salt, it may be converted to a free base according to a conventional method.

On the other hand, when the compound having the substituent is an acidic compound according to the type of the substituent exemplified above, it can be converted to a salt using a base according to a conventional method. The salt with a base may be a salt with any base as long as it does not hinder the reaction, such as a salt with an inorganic base, a salt with an organic base, and a basic amino acid. And salts with acids. Suitable examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt, ammonium salt and the like. . Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, jetanolamine, trin and the like. Preferable examples of the salt with a basic amino acid include salts with arginine, lysine, orditin and the like. When the obtained compound is a salt, it may be converted to a free acid according to a conventional method.

 The reaction described in the above (1) is performed, for example, under the following reaction conditions.

Expression

 Wherein each symbol is as defined above, or a salt thereof is subjected to a ring closure reaction in a solvent containing diester carbonate,

[Wherein each symbol is as defined above] or a salt thereof. The reaction described in the above (1) is preferably performed in the presence of a base. Examples of such a base include metal hydrides (eg, hydrides of alkali metals such as sodium hydride, potassium hydride, etc.), Metal hydrocarbons (eg, compounds having a chemical bond between C ^ ₄ alkyl and alkali metal such as n-butyllithium, etc.), Alcohols (eg, sodium methoxide, sodium ethoxide, sodium tobutoxy, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium methoxide, lithium ethoxide, lithium butoxide, etc. Alkali metal hydroxides (eg, NaOH, K0H, etc.), basic carbonates (eg, sodium salts, potassium salts, etc.) Alkali metal salts such as potassium salt and magnesium salt, etc., basic bicarbonate (eg, bicarbonate with alkali metal salts such as sodium salt, potassium salt, etc.), organic base (Eg, trimethylamine, triethylamine, diisopropylethylamine, pyridine, pico Phosphorus, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-di Azabicyclo [5.4.0] —7-ndecene, etc., among which metal hydrides (eg, sodium hydride, potassium hydride, etc.), alcoholates (eg, aOMe, NaOEi) , t-BuONa, t-BuOK, etc.) are preferred, and alcoholates (eg, NaOMe, NaOEt, t-BuONa, t-BuOK, etc.) are particularly preferred.

 The amount of the base used in the reaction described in the above (1) is about 0.1 to 100 equivalents, preferably 1 to 5 equivalents.

 Any reaction solvent may be used as long as it contains a carbonic acid diester.A single solvent of the carbonic acid diester, a mixed solvent of two or more carbonic acid diesters, or a mixture of any of these with a solvent other than the carbonic acid diester It may be a solvent or the like. As the carbonic acid diester, Z "-0 (CO) 0—Z '[wherein, Z" and Z' each represent an optionally substituted hydrocarbon group (preferably an optionally substituted alkyl group). The compound is liquid at the reaction temperature for carrying out the reaction. Z ″ and Z ′ are preferably the same. As the diester carbonate, dialkyl carbonate is preferable, and among them, dialkyl carbonate such as dimethyl carbonate and getyl carbonate is preferably used.

Used as a mixture with one or more carbonic acid diesters The solvent other than the above may be any solvent as long as it does not hinder the reaction, for example, a halogenated solvent (eg, methylene chloride, dichloroethane, chloroform, etc.), aliphatic Hydrocarbons (eg, n-hexane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), ethers (eg, tetrahydrofuran (THF), getyl ether, etc.), polar solvents (eg, Dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.), alcohols (eg, methanol, ethanol, propanol, isopropanol, n-butanol, 2-methoxyethanol, etc.), formate esters (eg, alkyl formate) Ester), oxalic acid ester (eg, dioxalic acid (^ -4 alkyl ester, etc.)) That is, among even, dimethylformamide (DMF), alcohols (e.g., methanol, etc. Etano one Le) and the like are preferably used.

 The reaction may be carried out using an appropriate mixed solvent, but the reaction is preferably carried out in a solvent containing a diester carbonate (preferably dimethyl carbonate or getyl carbonate).

 The reaction temperature is usually about −20 to 200 ° C., preferably about 10 to 100 ° C., and the reaction time is usually about 0.1 to 100 hours, preferably about 0.5 to 50 hours.

 The reaction described in the above (7) is carried out, for example, under the following reaction conditions.

Expression

 Wherein each symbol is as defined above, or a salt thereof is subjected to a ring closure reaction in a solvent containing diester carbonate,

R X

z [Wherein each symbol is as defined above] or a salt thereof. The reaction described in the above (7) can be carried out under the same conditions as in the reaction described in the above '(1). '

 The reaction described in (13) above is performed, for example, under the following reaction conditions.

Expression

 Wherein each symbol is as defined above, or a salt thereof is subjected to a ring closure reaction in a solvent containing a carbonic acid diester,

 [Wherein each symbol is as defined above] or a salt thereof. The reaction described in the above (13) can be performed under the same conditions as in the reaction described in the above (1).

 Formula obtained by the reaction described in (1) above

[Wherein each symbol is as defined above] or a salt thereof,

[In the formula, Z represents an electron-withdrawing group, W represents optionally substituted ethylene or optionally substituted vinylene, and when the ethylene or vinylene has two substituents, May combine with each other to form an optionally substituted ring, R ³ represents a hydrogen atom or an optionally substituted hydrocarbon group, and X ″ represents a straight-chain moiety having 4 or more atoms having 2 or more atoms. Or a salt thereof; or a salt thereof; and the like, are novel compounds not described in the literature.

 Further, the formula obtained by the reaction described in the above (1)

 The compound represented by the formula [wherein each symbol is as defined above] or a salt thereof is useful as a pharmaceutical, an agricultural chemical, a food, a cosmetic, a chemical, or an intermediate thereof. For example, the formula obtained by the reaction described in (1) above

[Wherein the symbols are as defined above] or a salt thereof, According to a method of knowledge (for example, the method described in JP-A-8-73476, W099 / 55690, JP-A-11-302267, JP-A-11-302270, WO99Z5142, etc.), Pharmaceuticals useful as a formation promoter, a NaH exchange inhibitor, a therapeutic agent for pollakiuria / urinary incontinence, a therapeutic agent for edema, a therapeutic agent for central disease, and the like can also be produced. BEST MODE FOR CARRYING OUT THE INVENTION

 The present invention is described in more detail with reference to the following Reference Examples and Examples. However, these are merely examples and do not limit the present invention in any way. Example

Synthesis of general 2-alkoxybenzaldehyde derivatives

 [Reference Example 1] 4- (2-formylphenoxy) butyric acid ethyl ester

 4-Ethyl 4-bromobutyrate (6.6 ml) was added to a suspension of salicylaldehyde (5.0 g) and potassium carbonate (6.2 g) in DMF (15 ml), and the mixture was stirred at 90 ° C. for 1 hour. The reaction solution was cooled to room temperature and neutralized with 1N hydrochloric acid. After extraction with ethyl acetate, the extract was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by a silica gel column (n-hexane / ethyl acetate = 4/1), the effective fraction was concentrated, and 4- (2-formylphenoxy) butyric acid ethyl ester of colorless oil (9.6 g, yield 99%) ).

E -丽_{R (CDC1 3, δ, 300MHz} ): 1.27 (3H, t, J = 7.1Hz), 2.14-2.23 (2H, m), 2.54 (2H, t, J = 7.2Hz), 4.11-4.18 ( 4H, m), 6.96-7.0 (2H, m), 7.52 (1H, dt, J = l.7, 7.1Hz), 7.82 (1H, dd, J = l.7, 7.7Hz), 10.49 (1H IR (neat, cm— ¹ ): 1733, 1687, 1598, 1243.

 In the same manner as in Reference Example 1, the compounds described in Reference Examples 2 to 4 were synthesized.

 [Reference Example 2] 4- (4-bromo-2-formylphenoxy) butyric acid ethyl ester

Colorless oil, 98% yield. _{'Η - NMR (CDC1 3,} δ, 300MHz): 1.23 (3Η, t, J = 7.1Hz), 2.11-2.20 (2H, m), 2.50 (2H, t, J = 7.2Hz), 4.08-4.16 ( 4H, m), 6.85 (1H, d, J = 8.9), 7.58 (1H, dd, J = 8.9, 2.6Hz), 7.88 (1H, d, J = 2.6Hz), 10.37 (1H, s) .IR (neat, cnf ¹ ): 1731, 1683, 1590, 1272.

[Reference Example 3] 4- (2-formyl-4-methoxyphenoxy) butyric acid ethyl ester colorless oil, yield 99%. 'H-NMR (CDC13 _> δ, 300MHz): 1.23 (3Η, t, J = 7.1Hz), 2.09-2.18 (2H, m), 2.50 (2H, t, J = 7.2Hz), 3.77 (3H, s), 4..05-4.15 (4H, m), 6.90 (IH, d, J = 9.1), 7.08 (IH, dd, J = 9.1, 3.2Hz), 7.30 (IH, d, J = 3.2Hz) ),

10.3 (IH, s) .IR (neat, cm- ¹ ): 1731, 1683, 1496, 1218.

[Reference Example 4] 5- (2-formyl-4-methoxyphenoxy) pentanoic acid ethyl ester colorless oil, yield 99%. 'Eta - field _{R (CDC1 3, δ, 300MHz} ): 1.21 (3Η, t, J = 7.1Hz), 1.80-1.87 (4H, i), 2.37 (2H, t, J = 7.1Hz), 3.77 (3H , s), 4.01-4.1 (4H, m), 6.89 (IH, d, J = 9.1Hz), 7.08 (IH, dd, J = 9.1, 3.2Hz), 7.29 (IH, d, J = 3.2Hz) ,

10.44 (IH, s) .IR (neat, cm- ¹ ): 1731, 1683, 1496, 1218.

Synthesis of general 2-formyl-N-methylaniline derivatives

 [Reference Example 5] 5- (4-bromo-2-formyl-N-methylanilino) pentanoic acid

 A suspension of 1-methyl-2-piperidone (5.0 g) in 4N sodium hydroxide (22.1 ml) was stirred for 8.5 hours under reflux with heating. After cooling to room temperature, concentrated hydrochloric acid (7.4 ml) was added. A solution of sodium carbonate (9.4 g) and 5-bromo-4-fluorobenzaldehyde (4.5 g) in DMS0 (74 ml) was added, and the mixture was stirred under heating and reflux for 1.5 hours. After cooling to room temperature, the pH was adjusted to about pH = 3.3 with 6N hydrochloric acid. After extraction with ethyl acetate, the extract was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated. The precipitated crystals were dissolved by heating in isopropyl ether [IPE] (i20 ml), allowed to cool to room temperature, and then stirred on ice for 1 hour. The crystals were filtered and washed with IPE. Drying under reduced pressure (40 ° C for 1 hour) gave yellow crystals of 5- (4-bromo-2-formyl-N-methylanilino) pentanoic acid (4.0 g, yield 57%).

Immediately 72-73 ° C. 'H-NM CCDClg, δ, 300MHz): 1.61-1.69 (4Η, m), 2.36 (2Η, t, J = 6.7Hz), 2.87 (3H, s), 3.13 (2H , t, J-6.9Hz), 6.97 (IH, d, J = 8.8Hz), 7.5 (IH, dd, J = 8.8, 2.5Hz), 7.86 (IH, d, J = 2.5Hz), 10.17 (IH _{, s) Anal Calcd for C 13} H 16 N0 3 Br:... C, 49.70; H, 5.13; N, 4.46; Br, 25.43 Found: C, 49.75; H, 5.16; N, 4.45; Br, 25.40. IR (KBr, cm- ¹ ): 1731, 1648.

In the same manner as in Reference Example 5, the compounds described in Reference Examples 6 to 8 were synthesized. [Reference Example 6] 5- (2 formyl-N-methylanilino) pentanoic acid

 Yellow oil, 37% yield. 'H-NMRCCDClj, δ, 300MHz): 1.64-1.73 (4Η, m), 2.38 (2H, t, J = 6.7Hz), 2.90 (3H, s), 3.17 (2H, t, J = 6.9Hz), 7.04-7.13 (2H, m), 7.50 (IH, dd, J = l.7, 5.5Hz), 7.80 (IH, dd, J = l.7, 7.7Hz), 10.28 (IH, s).

IR (neat, cm " ¹ ): 1708, 1683.

 [Reference Example 7] Formyl_4-nitro-N-methylanilino) pentanoic acid

Yellow crystals, 93% yield. . rap.107-108 ° C Ή - Awakening: _{R (CDC1 3, δ, 300MHz} ): 1.60-1.67 (2Η, m), 1.75-1.81 (2Η, m), 2.38 (2Η, t, J = 6.7Hz) , 2.90 (3H, s), 3.43 (2H, t, J = 7.4Hz), 6.98 (IH, d, J = 9.4), 8.20 (IH, dd, J -9.4, 2.8Hz), 8.58 (IH, d , J = 2.8Hz), 9.67 (IH, s). IR (Kbr, cm " ¹ ): 1704, 1677, 1598, 1324, 1307.

 [Reference Example 8] 6- (4-bromo-2-formyl-N-methylanilino) hexanoic acid

Yellow crystals, 80% yield. . mp.95- 96 ° C 'Η- Awakening: _{R (CDC1 3, <5,} 300MHz): 1.27-1.32 (2H, m), 1.54-1.66 (4H, m), 2.31 (2H, t, J = 7.4 Hz), 2.83 (3H, s), 3.08 (2H, t, J-7.5Hz), 6.93 (IH, d, J = 8.8Hz), 7.50 (IH, dd, J = 8.8, 2.5Hz), 7.83 ( IH, d, J = 2.5Hz), 10.12 (IH, s). Anal.Calcd for CH ₁₈ N0 ₃ Br: C, 51.23; H, 5.53; N, 4.27; Br, 24.35. Found: C, 51.25; H , 5.54; N, 4.21; Br, 24.48. IR (KBr, cm-g: 1720, 1644.

Synthesis of general 2-formyl-N-benzylaniline derivatives

 [Reference Example 9] 5- (4-butanemo-2-formyl-N-benzylanilino) pentanoic acid

To a solution of benzaldehyde (6. Og) in methanol (80 ml) was added 4-aminobutyric acid (6.6 g) and 1N sodium hydroxide (56.5 ml). After replacing the Kolben with argon, 20% Pd-C (wet, 0.6 g) was added. The Kolben was replaced with hydrogen and stirred at room temperature. Pd-C was collected by filtration and washed with methanol. 6N hydrochloric acid (9.4 ml) was added to the filtrate, and the mixture was concentrated to dryness. Then, sodium carbonate (12. Og) and DMS0 water (57 ml / 37 ml) were added, and a solution of 5-bromo-4-fluorobenzaldehyde (5.7 g) in DMS0 (17 ml) was added dropwise under heating and reflux. Stirred for hours. After cooling to room temperature, the pH was adjusted to about pH = 3.5 with 6N hydrochloric acid. After extraction with ethyl acetate, the extract was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated. After the concentrate was purified by a silica gel column (n-hexane / ethyl acetate = 4/1), the effective fraction was concentrated, and yellow oily 5- (4-bromo-2-formyl-N-benzylanilino) pentyl Acid (7.4 g, 61% yield) was obtained. Ή- Ran _{R (CDC1 3, δ, 300MHz} ): 1.52-1.65 (4H, m), 2.27-2.35 (2H, m), 3.08-3.15 (2H, m), 4.31 (2H, s), 7.01 (IH , d, J = 8.7Hz), 7.16-7.36 (5H, m), 7.57 (IH, dd, J = 8.7, 2.4Hz), 7.92 (IH, d, 1 = 2.4Hz), 10.36 (IH, s) EI-MS (M ⁺ ): 391.

IR (neat, cm " ¹ ): 1708, 1683.

 The compound described in [Reference Example 10] was synthesized in the same manner as in [Reference Example 9].

[Reference Example 10] 5- (4-Bromo-2-formyl-N-benzylanilino) heptanoic acid yellow oily substance, yield 27%. _{Ή- NMR (CDC1 3, δ,} 300MHz): 1.21-1.26 (4Η, m), 1.46- 1.56 (4H, m), 2.27 (2H, t, J = 7.4Hz), 3.05 (2H, t, J- 7.5Hz), 4.26 (2H, s), 6.97 (IH, d, J = 8.7Hz), 7.13-7.28 (5H, m), 7.51 (IH, dd, J-8.7, 2.5Hz), 7.87 (IH, d, J = 2.5Hz), 10.30 (IH, s) .IR (neat, cm ' ¹ ): 1706, 1683.

General ring closure reaction (met hod A)

 Example 1 Ethyl 2,3-dihydro-tolbenzoxepin-4-carboxylate Ethyl 4- (2-formylphenoxy) butyrate (2.4 g) was dissolved in a solution of ethyl carbonate (24 ml) at room temperature in 20% at room temperature. A sodium ethoxide ethanol solution (4.lg) was added, and the mixture was stirred at 50 ° C for 1 hour. Cooled to room temperature and neutralized with 1N hydrochloric acid. After extraction with ethyl acetate, the extract was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated. The concentrate is purified by a silica gel column (n-hexane / ethyl acetate = 10/1), the effective fraction is concentrated, and the colorless oily 2,3-dihydro-1-benzoxepin-4-carboxylic acid ethyl ester (1.3 g, yield 61%).

'H-NMR (CDC1 _3> δ, 300MHz): 1.36 (3Η, t, J = 7.1Hz), 2.97-3.00 (2H, m), 4.26- 4.31 (4H, m), 6.96-7.04 (2H, m ), 7.21-7.27 (IH, m), 7.32-7.35 (IH, m), 7: 58 (IH, s) .IR (neat, cm ' ¹ ): 1700, 1249.

 [Reference Example 11] 2,3-dihydro-1-benzoxepin-4-ethyl carboxylate

 To a solution of 4- (2-formylphenoxy) butyric acid ethyl ester (2.) in THF (24 ml) was added potassium tobutoxy (1.2 g) at room temperature, and the mixture was stirred at 50 ° C for 2 hours. Cooled to room temperature and neutralized with 1N hydrochloric acid. After extraction with ethyl acetate, the extract was washed with saturated saline. The organic layer was quantified by HPLC.

Quantitative value: 4- (2-formylphenoxy) butyric acid ethyl ester (0.1 lg, 4% yield), 4- (2-formylphenoxy) butyric acid ethyl ester Formylphenoxy) butyric acid (0.3 g, 14% yield), 2,3-dihydro-levenzoxepin-4-ethyl ethyl ester (0.4 g, 17% yield), 2,3-dihydro- There was obtained 1-benzoxepin-4-pyruonic acid (0.3 g, yield 15%).

 The compounds described in [Example 2] to [Example 4] were synthesized in the same manner as in [Example 1].

 Example 2 7-Bromo-2,3-dihydro-1-benzoxepin-4-carboxylic acid ethyl ester (method A)

White crystals, yield 34%. Soku .85-86 ° C Ή- negation _{R (CDC1 3, δ, 300MHz} ):. 1.3 (3Η, t, J-7.1Hz), 2.92-2.97 (2H, m), 4.19-4.25 (4H, m) , 6.82 (1H, d, J = 8.6Hz), 7.28 (1H, dd, J = 8.6, 2.4Hz), 7.42 (1H, d, J-2.4Hz), 7.43 (1H, s).

 Example 3 7-Methoxy-2,3-dihydro-1-benzoxepin-4-carboxylic acid ethyl ester (method A)

White crystals, yield 82%. Soku .62- 63 ° C Ή- NMR (CDC1 3, δ, 300MHz):. 1.32 (3Η, t, J = 7.1Hz), 2.92-2.95 (2H, m), 3.76 (3H, s), 4.17- 4.28 (4H, m), 6.77-6.81 (2H, m), 6.87 (1H, dd, J = 1.6, 7.4Hz), 7.49 (1H, s).

 Example 4 8-Methoxy-3,4-dihydro-2H-1-benzoxosin-5-carboxylic acid ethyl ester (method A)

Colorless oil, 11% yield. _{'H-NMR (CDC1 3,} δ, 300MHz):. 1 4 (3Η, t, J = 7.1Hz), 1.82-1.88 (2H, m), 2.66-2.70 (2H, m), 3.86 (3H, s ), 4.2 -4.39 (4H, m), 6.77 (1H, d, J = 3.0Hz), 6.92 (1H, dd, J = 3.0, 8.9Hz), 7.02 (1H, d, J = 8.9Hz), 7.70 (1H, s). IR (neat, cm " ¹ ): 1704, 1496, 1243.

General ring closure reaction (method B)

 [Example 5] 8-Bromo-trimethyl-1,, 3,4-tetrahydro-1-benzazosin-5_ force Rubonic acid methyl ester

To a solution of 5- (4-bromo-2-formyl-N-methylanilino) pentanoic acid (3.Og) in DMF (8 ml) was added potassium carbonate (1.6 g) and methyl iodide / DMF (1.6 g / 2 ml). The mixture was added at room temperature and stirred for 2 hours. Ethyl acetate and water were added and the mixture was separated and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain yellow oily methyl 5- (4-bromo-2-formyl-N-methylanilino) pentanoate (3.0 g, yield 97%). . ^l H-NMR (CDCl ₃ , δ, 300MHz): 1.58-1.64 (4H _f m), 2.28 (2H, t, J = 6.8Hz), 2.83 (3H, s), 3.09 (2H, t, J = 6.8 Hz), 3.63 (3H, s), 6.95 (1H, d, J = 8.8Hz), 7.51 (1H, dd, J = 8.8, 2.4Hz), 7.83 (1H, d, J = 2.4Hz), 10.14 ( 1H, s). FAB-MS ([M + Na] +): 350. IR (neat, cm " ¹ ): 1735, 1681.

To a solution of methyl 5- (4-bromo-2-formyl-N-methylanilino) pentanoate (3.Og) in dimethyl carbonate (40 ml) was added a 28% sodium methoxide methanol solution (2.3 g) at room temperature. And stirred at 50 hours. Cooled to room temperature and neutralized with 1N hydrochloric acid. After extraction with ethyl acetate, the extract was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by a silica gel column (n-hexane / ethyl acetate = 10/1), and the effective fraction was concentrated. The precipitated crystals were washed with IPE and collected by filtration. After drying under reduced pressure (40 ° C for 1 hour), 8-bromo-1-methyl-1,2,3,4-tetrahydro-tobenzazocin-5-carboxylic acid methyl ester of yellow crystals (0.9 g, 31% yield) I got Soku .88- 89 ° C 'H-NMR (CDC1 3, δ, 300MHz):.. 1 (2Η, m), 2.54 (2Η, t, J = 6.2Hz), 2.87 (3H, s), 3.42 ( 2H, t, J = 5.6Hz), 3.78 (3H, s), 6.56 (1H, d, J = 6.0Hz), 7.19-7.23 (2H, m), 7.68 (1H, s). Anal. Calcd for C ₁₄ H ₁₆ N0 ₂ Br: C, 54.21; H, 5.20; N, 4.52; Br, 25.76. Found: C, 54.19; H, 5.29; N, 4.37; Br, 25.74.

IR (KBr, cm- ¹ ): 1689, 1189.

 In the same manner as in [Example 5], the compounds described in [Example 6] to [Example 9] were synthesized.

 Example 6 1-Methyl-1,2,3,4-tetrahydro-1-benzazosin-5-carboxylic acid methyl ester (method B)

 5- (2-formyl-N-methylanilino) pentanoic acid methyl ester

Yellow oil, 99% yield. _{'H-NMR (CDC1 3,} δ, 300MHz): 1.58-1.68 (4Η, m), 2.30 (2H, t, J = 6.8), 2.86 (3H, s), 3.12 (2H, t, J = 6.8Hz ), 3.64 (3H, s), 7.01-7.10 (2H, m), 7.46 (1H, dt, J = L 7, 7.3Hz), 7.76 (1H, dd, J = l.7, 7.7Hz), 10.25 (1H, s) .IR (neat, cm ^-1 ): 1735, 1685, 1159.

Trimethyl-1,2,3,4-tetrahydro-1-benzazosin-5-carboxylic acid methyl ester

Yellow crystals, 30% yield. Immediately.80-82 ° C. 'H-NMRCCDClg, δ, 300MHz): 1.42-1.50 (2Η, -: '(S ¾I) 09' Z '(ω ^l ) U -Z-6l -L' (ΖΗ 9 = ί 'P' HDOA '9' (s

'Η8) ΑΑ Έ' (ζΗ6 · 9 = ί Ί "ΆΖ) ΖΙ 'S' (s ¾S) 9 'Z' (¾Η69 = ί Ί 'Η2) 08 Ί' (m 'Η2) 96 Ί-8 'ΐ' (ω ¾Z) '[-Ζ9 Ί: (ζ00S' Q ' ^s I0a3) NH, °% 8ΐumbrella "^ W ^

'g-1- ¾-6

"1891 '32 Ι · (,-αΐ3 '?) 31': ( ₊ WW]) SW-9Vd ¾ί) 0ί ΌΪ '(ΖΗ9 · Ζ = ί' Ρ Ήί) 08 '(' 8 · 8 = ί ' ΡΡ 'Ηΐ)' (ΖΗ8 '= ί' Ρ 'Ηΐ) ΐ6' 9 '(s' Η8) ΐ9 "S' (ΖΗ9 · 9 = ί '}' ΗΖ) 90 '8' (s ¾8) 18 '' I Ί 'Ζ) Η' (ω 'H) l9 "I -IS' (in 'HZ) 0S · 02 02 Ί: (zffiiOOS. (D) Leakage-°% 86 umbrella ¾l ^

-9 02

 (3 Ρ01Π3ΠΙ) f f 邈 ^

 -9- r vXX v-l-Hl-a? | '' 8 Ί-Λ (^ ^ -ΐ-¾α: -6 [8 P TO]

 'Thigh' 96fl

'i: (g U)' B3U) ¾I "Q8C: W) SW-I3 ¾1) SZ 'I' ('ΗΖ) 69" Z-60 Ά' (0 '6 = f

'P' Hl) 0S '9' (s ¾2) St 1 '(s ¾g) 18 -S' (ZHC "9 = 1 Ί ¾Z) 0S -8 '(ZHl' 9 = ί Ί SI

'HZ) 69' I '(ui ¾Z) 09' l-fΐ: (zffiWOS ' ^S I3 (K)) Lia-H, °% 9A

^ ^ Γ £ ί-9- ^ ΑΖ V-ΐ-α ^ 4-^-'2 1' u 8-ku ^-ΐ

Έ891 'Se l-''ϊ) I Έ0 ·· 13' (s

¾1) 9S 'ΟΙ Ί = ί' Ρ ¾ΐ) Ζ6 '(ΖΗ9 Ί Ί "8 = r' ΡΡ 'Ηΐ) 99 Ί' (πι ¾9) 28 Ά-ΑΙ ΟΤ '(L" 8 = 1' Ρ 'Ηΐ ) ΐθ "A '(s ¾2) IS 1' (s ¾8) 99 Έ '(ΖΗ9" 9 = ί Ί' ΕΖ) Ζ \ '8' H · 9 = ί Ί ¾ Z '(ω ¾) 09!: (ZHPJ00S '9' ^ε Ι 303) Μ-Η, °% 001 ί ^ ¾¾¾

 N v-N-ir $ ΊΓ ^ -2-¾ Π -g

-9- / .ζ -ΐ-πΗ

ζ

 "68 Π

'9891: (, -Uio' mm '90 "9 'N: 99 · ί' Η: 00 Έ Ό: puno ^ · 90 '9' Ν: ke · ί 'Η: 0 · 1ί' 3: W'H ^ O JOj ροΐ¾3 '两-(s' HI) 08 Ί '(ω' Ζ) ΖΖ -U Ί '(πι Z) U' 9-Z9 -9 '(s ¾S) 6 A "2' (ZH -S = f Ί 'HZWS' (s ¾8) 06 '(ZHZ "9 = f Ί' HZ S '(m

 τε

06llO / TOdf / X3d 89 polishing ΪΟ OAV IR (neat, cm— ¹ ): 1708, 1494.

General ring closure method (method 0

 [Example 9] 8-Nitro-1-methyl-1,2,3,4-tetrahydro-1-benzazosin-5-force rubonic acid methyl ester

 To a solution of 5- (2-formyl-4-nitro-N-methylanilino) pentanoic acid (3. Og) in DMF (8.lml), add potassium carbonate (1.6g) and methyl iodide / DMF (1.8g / lml) The solution was added at room temperature and stirred for 2 hours as it was. A dimethyl carbonate (18 ml) solution and then a 28% sodium methoxide methanol solution (5. Og) were added to the reaction solution, and the mixture was stirred at 50 ° C for 2.5 hours. It was cooled to room temperature and neutralized with 1N hydrochloric acid. After extraction with ethyl acetate, the extract was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The concentrate was dissolved by heating in isopropyl alcohol [IPA] and then allowed to cool to room temperature. The mixture was further stirred at room temperature for 1 hour and ice-cooled for 0.5 hour. The precipitated crystals were collected by filtration, and the crystals were washed with IPA. The crystals were purified by a silica gel column (n-hexane / ethyl acetate = 2 / 1—1 / 1), and the effective fraction was concentrated and yellow crystals of 8-nitro-1_methyl-1,2,3,4-tetrahydro -1-Benzazocin-5-carboxylic acid methyl ester (2.3 g, yield 78%) was obtained.

. mp.127-129 ° C 'H-NMR (CDC1 3, 6, 300MHz): 1.38-1.72 (2H, m), 2.35-2.80 (2H, m), 3.02 (3H, s), 3.42-3.85 ( 2H, m), 3.80 (3H, s), 6.65 (IH, d, J = 9.4Hz), 7.80 (IH, s), 7.99-8.06 (2H, m). Anal.Calcd for C ₁₄ H ₁₆ N ₂ 0 ₂ : C, 60.86; H, 5.84; N, 10.14. Found: C, 60.79; H, 5.81;, 9.98.IR (KBr, cm " ¹ ): 1708, 1255, 1191.

 The compound described in [Example 10] was synthesized in the same manner as in [Example 9].

 Example 10 1-Benzyl-10-bromo-1,2,3,4,5,6_hexahydro-1-benzazecin-7-carboxylic acid methyl ester (method 0

Yellow oil, 6% yield. Ή- noodles _{R (CDC1 3, δ, 300MHz} ): 1.24-1.29 (2Η, m), 1.44- 1.50 (2H, m), 1.57-1.63 (2H, m), 2.13 (2H, t, J = 6.5Hz ), 2.89 (2H, t, J = 6.2Hz) ', 3.48 (3H, s), 3.90 (2H, s), 7.02 (IH, d, J = 8.6Hz), 7.10-7.25 (6H, m), 7.37 (IH, dd, J = 8.6, 2.4), 7.48 (IH, s). 贿 Br, cm " ¹ ): 1712, 1279, 1232.

 [Reference Example 11]

 Synthesis of 4'-ethoxy-4-hydroxy-1, Γ-biphenyl-3-carbaldehyde

Under an argon atmosphere, tribromo-4-ether was added to a suspension of magnesium (0.5 g) in THF (7 ml). A solution of xylene (4. Og) in THF (2.5 ml) was slowly added dropwise at room temperature, and the mixture was stirred for 1 hour. At −10 to 10 ° C., a solution of trimethoxyporane (2.lg) in THF (2.5 ml) was added dropwise, further THF (7 ml) was added, and the mixture was stirred for 1 hour while maintaining the same temperature. The temperature was raised to room temperature, and a solution of tetrakistriphenylphosphine palladium (115 mg), 5-bromo-2-hydroxybenzaldehyde (2.Og) and tripotassium phosphate (11.lg) in water (15 ml) was added. The mixture was stirred under heat reflux for 1 hour. After cooling to room temperature, 6N hydrochloric acid (20 ml) was added dropwise, and then toluene (20 ml) was added. After liquid separation, toluene (30 ml) was further extracted from the aqueous layer. The organic layers were combined and washed with 10 saline (10 ml × 3). It was dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (n-hexane / ethyl acetate = 6/1), and the effective fraction was concentrated. Diisopropyl ether (15 ml) was added to the concentrate, and the mixture was heated under reflux and allowed to cool to room temperature. n-Hexane (15 ml) was added, and the mixture was stirred at room temperature for 1 hour and under ice cooling for 0.5 hour. The precipitated crystals were collected by filtration, washed with a solution of diisopropyl ether / n-hexane (1/1, 4 ml) cooled to (! To 5), dried under reduced pressure (room temperature, 2 hours), and dried to give yellow crystals. 1.8 g (yield 73%) of the title compound was obtained.

94-95 ° C

_{. Anal Calcd for C 15 H 14} 0 3: C, 74. 36; H, 5. 82. Found: C, 74. 61; H, 5. 80. IR (KBr, cm- Ri 1660, 1473, 1276, 1245, 1047, 831.

_{'H-NMR (CDC1 3,} 300MHz) 6 1. 44 (3H, t, J = 7. 0Hz), 4. 07 (2H, q, J = 7. 0Hz), 6. 96 (2H, dd, J = l. 9,6.7 Hz), 7.04 (1H, d, J = 8.4 Hz), 7.45 (2H, dd, J = L 9,6.7 Hz), 7.68-7.77 (2H, m), 9.95 (1H, s), 10.95 (1H, s).

 [Reference Example 1 2]

 Synthesis of 4-[(4'-ethoxy-3-formyl-1,1-Γ-biphenyl-4-yl) oxy] ethyl ester

To a solution of 4'-ethoxy-4-hydroxy-1,1'-biphenyl-3-carpaldehyde (1.0 g) and 4-bromoethyl ester (0.9 g) in DMF (5 ml) was added potassium carbonate at room temperature. (1. lg) was added, and the mixture was stirred at room temperature for 14 hours and at 50 ° C for 3 hours. After cooling to room temperature, water (10 ml) was added, and the mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with water (10 ml × 3) and concentrated. Diisopropyl ether (14 ml) was added to the concentrate, and the mixture was refluxed under heating and allowed to cool to room temperature. Then, the mixture was stirred at room temperature for 1 hour and ice-cooled for 1 hour. The precipitated crystals are collected by filtration and brought to 0-5 ° C. The solution was washed with a cooled solution of diisopropyl ether (3 ml). The crystals were dried under reduced pressure (room temperature, 2 hours) to give 1.3 g (yield 91%) of the title compound as white crystals.

Melting point 69-70 ° C

_{. Anal Calcd for C 21 H 24} 0 5:. C, 70.77; H, 6.79 Found:. C, 70.91; H, 7.08 IR (KBr, cur 1) 1683, 1606, 1471, 1270, 1240, 1187, 1047.

'H-NMRCCDClg, 300MHz) δ 1.26 (3H, t, J = 7.1Hz), 1.43 (3H, t, J = 7.0Hz), 2.18-2.25 (2H, m), 2.56 (2H, t, J = 7.1 Hz), 4.04-4.20 (6H, ra), 6.94 (2H, dd, J = l.9, 6.7Hz), 7.03 (1H, d, J = 8.7Hz), 7.47 (2H, dd, J = l. 9, 6.7Hz), 7.72 (1H, dd, J = 8.7, 2.5Hz), 8.02 (1H, d, J = 2.5Hz), 10.53 (1H, s).

 [Example 11]

 7- (4-ethoxyphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid ethyl ester

 To a solution of 4-[(4'-ethoxy-3-formyl-1, 1-biphenyl-4-yl) oxy] ethyl ester (0.50 g) in getyl carbonate (5 ml) was added 20% sodium ethyl acetate. An ethanol solution (0.57 g) was added at room temperature, then the temperature was raised to 50 ° C., and the mixture was stirred for 1 hour. After neutralization with 1N hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated. After the concentrate was purified by silica gel chromatography (n-hexane / ethyl acetate = 10/1), the effective fraction was concentrated to obtain 0.39 g (yield: 82%) of the title compound as white crystals. .

Melting point 128-129 ° C

_{. Anal Calcd for C 21 H 22} 0 4:. C, 74.54; H, 6.55 Found:. C, 74.32; H, 6.46 IR KBr, cur 1) 1702, 1496, 1251, 1213.

Ichikaku _{R (CDC1 3, 300MHz) 6} 1.37 (3H, t, J = 7.1Hz), 1.44 (3H, t, J = 7.0Hz), 2.99-3.02 (2H, m), 4.07 (2H, q, J = 7.0Hz), 4.26-4.32 (4H, m), 6.95 (2H, dd, J = 1.9, 6.7Hz), 7.00 (1H, d, J = 8.4Hz), 7.41-7.51 (4H, m) , 7.65 (1H, s). Industrial applicability

 According to the present invention, it is possible to produce a cyclic compound in a short process, safely, and by a method suitable for mass synthesis.

Claims

The scope of the claims

1 set

[In the formula, Z represents an electron-withdrawing group, W represents optionally substituted ethylene or optionally substituted vinylene, and when the ethylene or vinylene has two substituents, May combine to form an optionally substituted ring, R ³ represents a hydrogen atom or an optionally substituted hydrocarbon group, and X represents a divalent group (provided that W is substituted X—CH ₂ _Z is one X ¹ —X ² _CH ₂ _Z (wherein X ¹ represents a sulfur atom or an optionally substituted nitrogen atom; X ² Represents an optionally substituted ethylene), but not subject to) a compound represented by the formula or a salt thereof in a solvent containing a carbonic acid diester in a ring-closing reaction:

 [Wherein the symbols are as defined above] or a method for producing a salt thereof.

 2. The production method according to claim 1, wherein X is a divalent group having 1 to 12 atoms in a straight chain portion.

3. The method according to claim 1, wherein Z is an esterified hydroxyl group.

4. The production method according to claim 1, wherein R ³ is a hydrogen atom.

 5. The process according to claim 1, wherein the reaction is carried out in the presence of a base.

6. The method according to claim 5, wherein the base is an alcoholate.

7. Expression

[In the formula, Z represents an electron withdrawing group, and R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, or an optionally substituted thiol. A group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, wherein R ¹ and R ² may combine to form an optionally substituted ring, and R ³ represents Represents a hydrogen atom or a hydrocarbon group which may be substituted, a combination of a broken line and a solid line represents a single bond or a double bond, and X represents a divalent group (however, a combination of a broken line and a solid line represents a double bond Where _X—CH ₂ —Z is one X ¹ —X ² one CH ₂ —Z (wherein X ¹ is a sulfur atom or an optionally substituted nitrogen atom, and X ² is a substituted ) Is not used.) Not a compound represented by the formula or a salt thereof. A ring closure reaction in a solvent containing ter,

 [Wherein the symbols are as defined above] or a method for producing a salt thereof.

 8. The method according to claim 1, wherein X is a divalent group having 1 to 12 atoms in a straight chain portion.

9. The method according to claim 7, wherein Z is an esterified hydroxyl group.

10. The method according to claim 7, wherein R ³ is a hydrogen atom.

 1 1. The production method according to claim 7, wherein the reaction is performed in the presence of a base.

 12. The production method according to claim 11, wherein the base is alcoholate.

13. Expression

[Wherein, Z represents an electron withdrawing group, R ³ represents a hydrogen atom or a hydrocarbon group which may be substituted, a combination of a dashed line and a solid line represents a single bond or a double bond, and ring A is substituted X represents a divalent group (however, ring A represents a benzene ring which may be substituted, and when a combination of a broken line and a solid line represents a double bond, X—CH ₂ — Z is — X ¹ — X ² _CH ₂ — Z (wherein X ¹ represents a sulfur atom or an optionally substituted nitrogen atom, and X ² represents an optionally substituted ethylene. Wherein the compound or its salt is subjected to a ring-closure reaction in a solvent containing a carbonic acid diester.

 [Wherein the symbols are as defined above] or a method for producing a salt thereof.

14. The production method according to claim 13, wherein X is a divalent group having 1 to 12 atoms in the straight-chain portion.

 15. The method according to claim 13, wherein Z is an esterified hydroxyl group.

16. The production method according to claim 13, wherein R ³ is a hydrogen atom.

 17. The process according to claim 13, wherein the reaction is carried out in the presence of a base.

18. The method according to claim 17, wherein the base is alcoholate.

19. Expression

[In the formula, Z represents an electron-withdrawing group, W represents optionally substituted ethylene or optionally substituted vinylene, and when the ethylene or vinylene has two substituents, May combine with each other to form an optionally substituted ring, R ³ represents a hydrogen atom or an optionally substituted hydrocarbon group, and X ″ represents a straight-chain moiety having 4 or more atoms having 2 or more atoms. Or a salt thereof.